Search

Isolated mesenteric artery dissection (IMAD) is an increasingly diagnosed disease. However, multicentre studies to support clinical decision making are limited. This multicentre retrospective study aimed to investigate the characteristics, treatment options, and outcomes of IMAD.Data from consecutively enrolled patients with IMAD between October 2009 and May 2021 at three hospitals were collected retrospectively. One hundred and ninety uncomplicated symptomatic IMAD patients were divided into two groups: conservative (n = 141) and operative (n = 49). The costs, length of hospital stay, factors affecting outcomes, symptom relief, and complete remodelling of superior mesenteric artery (SMA) were analysed between the two groups.Compared with patients who received operative treatment, patients receiving conservative treatment had shorter hospital stays (8.2 ± 4.6 vs. 11.9 ± 6.4 day, p.020) and lower hospital costs (14 900 ± 1 048 vs. 60 400 ± 7 733 yuan, p.001). In contrast, patients receiving operative treatment showed higher complete SMA remodelling (95.9% vs. 51.8%, p.001). The cumulative rate of symptom relief was similar between the groups (p = .71). The rates were 78% vs. 79%, 87% vs. 87%, 89% vs. 87% at one, 12, and 60 months in the conservative and operative groups, respectively. Further subgroup analysis showed that endovascular treatment of IMAD had the advantage of shorter hospital stays than open surgery (10.7 ± 4.5 vs. 25.2 ± 9.4 days, p.010). Univariable analysis showed that Sakamoto type II was associated with failed complete SMA remodelling (odds ratio 0.34; 95% confidence intervals 0.13 - 0.91; p = .031).IMAD patients achieved good long term survival and symptom relief regardless of the treatment. Sakamoto type II IMAD is a risk factor for failed complete SMA remodelling. Although endovascular treatment provided a higher rate of complete SMA remodelling, the conservative group had statistically significantly shorter hospital stays, lower hospital costs, and similar cumulative rates of symptom relief. Therefore, this study supports conservative treatment as the main strategy for uncomplicated symptomatic IMAD patients.

Objective: Vascular endothelial cells (ECs) play a critical role in maintaining vascular homeostasis. Aberrant EC metabolism leads to vascular dysfunction and metabolic diseases. TFEB (transcription factor EB), a master regulator of lysosome biogenesis and autophagy, has protective effects on vascular inflammation and atherosclerosis. However, the role of endothelial TFEB in metabolism remains to be explored. In this study, we sought to investigate the role of endothelial TFEB in glucose metabolism and underlying molecular mechanisms. Approach and Results: To determine whether endothelial TFEB is critical for glucose metabolism in vivo, we utilized EC-selective TFEB knockout and EC-selective TFEB transgenic mice fed a high-fat diet. EC-selective TFEB knockout mice exhibited significantly impaired glucose tolerance compared with control mice. Consistently, EC-selective TFEB transgenic mice showed improved glucose tolerance. In primary human ECs, small interfering RNA-mediated TFEB knockdown blunts Akt (AKT serine/threonine kinase) signaling. Adenovirus-mediated overexpression of TFEB consistently activates Akt and significantly increases glucose uptake in ECs. Mechanistically, TFEB upregulates IRS1 and IRS2 (insulin receptor substrate 1 and 2). TFEB increases IRS2 transcription measured by reporter gene and chromatin immunoprecipitation assays. Furthermore, we found that TFEB increases IRS1 protein via downregulation of microRNAs (miR-335, miR-495, and miR-548o). In vivo, Akt signaling in the skeletal muscle and adipose tissue was significantly impaired in EC-selective TFEB knockout mice and consistently improved in EC-selective TFEB transgenic mice on high-fat diet. Conclusions: Our data revealed a critical role of TFEB in endothelial metabolism and suggest that TFEB constitutes a potential molecular target for the treatment of vascular and metabolic diseases.

Background: Abdominal aortic aneurysm (AAA) is a severe aortic disease with a high mortality rate in the event of rupture. Pharmacological therapy is needed to inhibit AAA expansion and prevent aneurysm rupture. Transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, is critical to maintain cell homeostasis. In this study, we aim to investigate the role of vascular smooth muscle cell (VSMC) TFEB in the development of AAA and establish TFEB as a novel target to treat AAA. Methods: The expression of TFEB was measured in human and mouse aortic aneurysm samples. We used loss/gain-of-function approaches to understand the role of TFEB in VSMC survival and explored the underlying mechanisms through transcriptome and functional studies. Using VSMC-selective Tfeb knockout mice and different mouse AAA models, we determined the role of VSMC TFEB and a TFEB activator in AAA in vivo. Results: We found that TFEB is downregulated in both human and mouse aortic aneurysm lesions. TFEB potently inhibits apoptosis in VSMCs, and transcriptome analysis revealed that TFEB regulates apoptotic signaling pathways, especially apoptosis inhibitor B-cell lymphoma 2. B-cell lymphoma 2 is significantly upregulated by TFEB and is required for TFEB to inhibit VSMC apoptosis. We consistently observed that TFEB deficiency increases VSMC apoptosis and promotes AAA formation in different mouse AAA models. Furthermore, we demonstrated that 2-hydroxypropyl-β-cyclodextrin, a clinical agent used to enhance the solubility of drugs, activates TFEB and inhibits AAA formation and progression in mice. Last, we found that 2-hydroxypropyl-β-cyclodextrin inhibits AAA in a VSMC TFEB–dependent manner in mouse models. Conclusions: Our study demonstrated that TFEB protects against VSMC apoptosis and AAA. TFEB activation by 2-hydroxypropyl-β-cyclodextrin may be a promising therapeutic strategy for the prevention and treatment of AAA.

Summary The rs58542926C >T (E167K) variant of the transmembrane 6 superfamily member 2 gene (TM6SF2) is associated with increased risks for nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Nevertheless, the role of the TM6SF2 rs58542926 variant in glucose metabolism is poorly understood. We performed a sex-stratified analysis of the association between the rs58542926C >T variant and T2D in multiple cohorts. The E167K variant was significantly associated with T2D, especially in males. Using an E167K knockin (KI) mouse model, we found that male but not the female KI mice exhibited impaired glucose tolerance. As an ER membrane protein, TM6SF2 was found to interact with inositol-requiring enzyme 1 α (IRE1α), a primary ER stress sensor. The male Tm6sf2 KI mice exhibited impaired IRE1α signaling in the liver. In conclusion, the E167K variant of TM6SF2 is associated with glucose intolerance primarily in males, both in humans and mice., Graphical abstract, Highlights • The TM6SF2 E167K variant is significantly associated with T2D, primarily in males • Male, but not female, Tm6sf2 KI mice exhibited impaired glucose tolerance • IRE1α signaling is attenuated in the liver of male Tm6sf2 KI mice • IDE and LIPIN1 were dysregulated in the liver of male KI mice but not the females, Physiology; Molecular physiology; Diabetology; Genomics

Endothelial cell (EC) dysfunction is a crucial initiation event in the development of atherosclerosis and is associated with diabetes mellitus, hypertension, and heart failure. Both digestive and oxidative inflammatory conditions lead to the endogenous formation of nitrated derivatives of unsaturated fatty acids (FAs) upon generation of the proximal nitrating species nitrogen dioxide (·NO2) by nitric oxide (·NO) and nitrite-dependent reactions. Nitro-FAs (NO2-FAs) such as nitro-oleic acid (NO2-OA) and nitro-linoleic acid (NO2-LA) potently inhibit inflammation and oxidative stress, regulate cellular functions, and maintain cardiovascular homeostasis. Recently, conjugated linoleic acid (CLA) was identified as the preferential FA substrate of nitration in vivo. However, the functions of nitro-CLA (NO2-CLA) in ECs remain to be explored. In the present study, a distinct transcriptome regulated by NO2-CLA was revealed in primary human coronary artery endothelial cells (HCAECs) through RNA sequencing. Differential gene expression and pathway enrichment analysis identified numerous regulatory networks including those related to the modulation of inflammation, oxidative stress, cell cycle, and hypoxic responses by NO2-CLA, suggesting a diverse impact of NO2-CLA and other electrophilic nitrated FAs on cellular processes. These findings extend the understanding of the protective actions of NO2-CLA in cardiovascular diseases and provide new insight into the underlying mechanisms that mediate the pleiotropic cellular responses to NO2-CLA.

Krüppel-like factors (KLFs) play essential roles in multiple biological functions, including maintaining vascular homeostasis. KLF11, a causative gene for maturity-onset diabetes of the young type 7, inhibits endothelial activation and protects against stroke. However, the role of KLF11 in venous thrombosis remains to be explored. Utilizing stasis-induced murine deep vein thrombosis (DVT) model and cultured endothelial cells (ECs), we identified an increase of KLF11 expression under prothrombotic conditions both in vivo and in vitro. The expression change of thrombosis-related genes was determined by utilizing gain- and loss-of-function approaches to alter KLF11 expression in ECs. Among these genes, KLF11 significantly downregulated tumor necrosis factor-α (TNF-α)-induced tissue factor (TF) gene transcription. Using reporter gene assay, chromatin immunoprecipitation assay, and co-immunoprecipitation, we revealed that KLF11 could reduce TNF-α-induced binding of early growth response 1 (EGR1) to TF gene promoter in ECs. In addition, we demonstrated that conventional Klf11 knockout mice were more susceptible to developing stasis-induced DVT. These results suggest that under prothrombotic conditions, KLF11 downregulates TF gene transcription via inhibition of EGR1 in ECs. In conclusion, KLF11 protects against venous thrombosis, constituting a potential molecular target for treating thrombosis.

Abdominal aortic aneurysm (AAA) is a life-threatening degenerative vascular disease. Endothelial cell (EC) dysfunction is implicated in AAA. Our group recently demonstrated that Kruppel-like factor 11 (KLF11) plays an essential role in maintaining vascular homeostasis, at least partially through inhibition of EC inflammatory activation. However, the functions of endothelial KLF11 in AAA remain unknown. Here we found that endothelial KLF11 expression was reduced in the ECs from human aneurysms and was time dependently decreased in the aneurysmal endothelium from both elastase- and Pcsk9/AngII-induced AAA mouse models. KLF11 deficiency in ECs markedly aggravated AAA formation, whereas EC-selective KLF11 overexpression markedly inhibited AAA formation. Mechanistically, KLF11 not only inhibited the EC inflammatory response but also diminished MMP9 expression and activity and reduced NADPH oxidase 2-mediated production of reactive oxygen species in ECs. In addition, KLF11-deficient ECs induced smooth muscle cell dedifferentiation and apoptosis. Overall, we established endothelial KLF11 as a potentially novel factor protecting against AAA and a potential target for intervention in aortic aneurysms.

Objective: Currently, there are no approved drugs for abdominal aortic aneurysm (AAA) treatment, likely due to limited understanding of the primary molecular mechanisms underlying AAA development and progression. BAF60a—a unique subunit of the SWI/SNF (switch/sucrose nonfermentable) chromatin remodeling complex—is a novel regulator of metabolic homeostasis, yet little is known about its function in the vasculature and pathogenesis of AAA. In this study, we sought to investigate the role and underlying mechanisms of vascular smooth muscle cell (VSMC)–specific BAF60a in AAA formation. Approach and Results: BAF60a is upregulated in human and experimental murine AAA lesions. In vivo studies revealed that VSMC-specific knockout of BAF60a protected mice from both Ang II (angiotensin II)–induced and elastase-induced AAA formation with significant suppression of vascular inflammation, monocyte infiltration, and elastin fragmentation. Through RNA sequencing and pathway analysis, we found that the expression of inflammatory response genes in cultured human aortic smooth muscle cells was significantly downregulated by small interfering RNA–mediated BAF60a knockdown while upregulated upon adenovirus-mediated BAF60a overexpression. BAF60a regulates VSMC inflammation by recruiting BRG1 (Brahma-related gene-1)—a catalytic subunit of the SWI/SNF complex—to the promoter region of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) target genes. Furthermore, loss of BAF60a in VSMCs prevented the upregulation of the proteolytic enzyme cysteine protease CTSS (cathepsin S), thus ameliorating ECM (extracellular matrix) degradation within the vascular wall in AAA. Conclusions: Our study demonstrated that BAF60a is required to recruit the SWI/SNF complex to facilitate the epigenetic regulation of VSMC inflammation, which may serve as a potential therapeutic target in preventing and treating AAA.

Objective— Mutations in Krüppel like factor-11 ( KLF11 ), a gene also known as maturity-onset diabetes mellitus of the young type 7, contribute to the development of diabetes mellitus. KLF11 has anti-inflammatory effects in endothelial cells and beneficial effects on stroke. However, the function of KLF11 in the cardiovascular system is not fully unraveled. In this study, we investigated the role of KLF11 in vascular smooth muscle cell biology and arterial thrombosis. Approach and Results— Using a ferric chloride–induced thrombosis model, we found that the occlusion time was significantly reduced in conventional Klf11 knockout mice, whereas bone marrow transplantation could not rescue this phenotype, suggesting that vascular KLF11 is critical for inhibition of arterial thrombosis. We further demonstrated that vascular smooth muscle cell–specific Klf11 knockout mice also exhibited significantly reduced occlusion time. The expression of tissue factor (encoded by the F3 gene), a main initiator of the coagulation cascade, was increased in the artery of Klf11 knockout mice, as determined by real-time quantitative polymerase chain reaction and immunofluorescence. Furthermore, vascular smooth muscle cells isolated from Klf11 knockout mouse aortas showed increased tissue factor expression, which was rescued by KLF11 overexpression. In human aortic smooth muscle cells, small interfering RNA–mediated knockdown of KLF11 increased tissue factor expression. Consistent results were observed on adenovirus-mediated overexpression of KLF11. Mechanistically, KLF11 downregulates F3 at the transcriptional level as determined by reporter and chromatin immunoprecipitation assays. Conclusions— Our data demonstrate that KLF11 is a novel transcriptional suppressor of F3 in vascular smooth muscle cells, constituting a potential molecular target for inhibition of arterial thrombosis.